KIT mutations have been linked to gastrointestinal stromal tumors (GISTs), testicular seminoma, mast cell disease, melanoma, and acute myeloid leukemia (AML).
In healthy cells, the protein that KIT encodes serves as a bouncer, letting certain molecules into the cell that tell the cell to divide. When mutated, the KIT protein can let in too many messengers, leading to unchecked cell growth.
There are therapies in clinical trials to treat conditions associated with KIT mutations. These include drugs called tyrosine kinase inhibitors, which target hyperactive KIT proteins in cancer.
Testing for a KIT mutation requires a sample of the cancer, ideally taken during a recent biopsy.
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As with many genes involved in cancer diagnoses, KIT is short for a mouthful: “v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog,” named after William Hardy and Evelyn Zuckerman, two scientists who researched the feline sarcoma virus. As its name would suggest, the feline sarcoma virus affects cats. What does a cat virus have to do with genetic mutations in humans? It was through these viruses that researchers were able to begin understanding exactly how mutations to this gene region cause problems in the biological functions of humans.
The KIT gene is the blueprint for a protein structure that we’ll call the KIT protein. Mutations in the KIT gene have been linked to gastrointestinal stromal tumors, testicular seminoma, mast cell disease, melanoma, and acute myeloid leukemia.
In a working human cell, the KIT protein is embedded in the cell membrane and acts like the gateway between the outside world and a private club. Like any good bouncer, its job is to field messages from outside the cell and only let in the cellular signals that are on the list. This list is determined by the shape and chemical makeup of the signal molecules, called ligands. Ligands floating outside may line up at KIT’s door, but only ones that meet the specific requirements of the KIT protein will get through.
The KIT protein is one of many doorways into the cell, each with a specific purpose—some bring in food for the cell, others information. But KIT, which is classified as a “receptor tyrosine kinase type III,” will only let in ligands called “stem cell factors.” The ligands do this chemically by binding with the KIT protein bouncer—which acknowledges that the stem cell factor is indeed on the list—and paying a cover charge of one ATP molecule, the ultimate intracellular currency. A message is then relayed by cellular messengers conveying that—party on—it is time to divide.
While every cell in the human body contains the same set of DNA and has the ability to produce the KIT protein, it is the blood-producing stem cells found in the bone marrow, as well as the stem cells responsible for the production of those cells, that are the most prominent. KIT is also active in adult stem cells responsible for replenishing the millions of cells we cycle through daily in our guts, and in skin cell production.
Back to our club analogy, normally functioning KIT genes produce bouncers with the proper training. These KIT proteins accept signals from stem cell factors, relay the message that the party is on, and cause the cell to divide and produce healthy blood and tissues. But two major kinds of mutations to the KIT gene can result in a variety of problems, some from birth and some later down the line.
The first kind of mutation is an activating mutation, which produces a KIT protein that gets stuck in the “go ahead” position and inappropriately conveys energetic signals instructing cells to divide faster and more than they should normally. Sometimes this may also delay the signals that drive an old cell to its naturally programmed death. In other words, the bouncer is drunk and letting everyone into the party, even when it is past closing time. This uncontrolled cell growth and proliferation results in tumors—specifically melanoma, testicular germ cell tumors, and gastrointestinal stromal tumors. Other mutations on KIT can cause acute myeloid leukemia, which results when faulty KIT proteins on blood-producing cells mandate the overproduction of white blood cells.
Conversely, some people have inactivating mutations on the KIT gene, which prevents the KIT protein from doing its job at all. In this case, the bouncer is asleep inside the club and the door is locked so no one can get in, even if they are on the guest list. This is a much rarer KIT mutation and is passed down from parent to child. The result is piebaldism, a genetic disorder in which the pigment called melanin, found in the skin, eyes, hair, and other less-visible organs, is unable to form during development. This results in scattered splotches of pigmentless skin on the body, a rogue streak of white in the hair, and a characteristic white triangle on the forehead.
There are a variety of new therapies being explored in clinical trials today to treat conditions associated with KIT mutations. One such treatment is called a tyrosine kinase inhibitor, which specifically targets the hyperactive KIT proteins in cancerous cells and blocks them from sending energetic signals into the cell.
Imatinib, dasatinib, and nilotinib (marketed as Gleevec, Sprycel, and Tasinga respectively) are all drugs in this category used to treat acute myeloid leukemia; each has a slightly different chemical makeup that may result in different levels of efficacy and side effects.
Sorafenib (marketed as Nexavar) is a kinase inhibitor, which blocks the action of other kinds of kinases in addition to tyrosine kinases like KIT. Sunitinib (Sutent) is a multi-targeted receptor tyrosine kinase inhibitor approved for use on two different kinds of receptor-related cancers and used when someone is resistant to imatinib.
Ultimately, the kind of treatment you undergo should be discussed at length with your oncologist to ensure that you understand all the possibilities and side effects associated with each course of action.